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Drug Metabolism and Disposition Fast Forward
First published on July 24, 2008; DOI: 10.1124/dmd.108.021857

0090-9556/08/3610-2104-2112$20.00
DMD 36:2104-2112, 2008

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Biotransformation of the Chemopreventive Agent 2',4',4-Trihydroxychalcone (Isoliquiritigenin) by UDP-Glucuronosyltransferases

Jian Guo, Ang Liu, Hongmei Cao, Yan Luo, John M. Pezzuto, and Richard B. van Breemen

Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, Chicago, Illinois (J.G., A.L., H.C., Y.L., R.B.v.B.); and School of Pharmacy, University of Hawaii at Hilo, Hilo, Hawaii (J.M.P.)

2',4',4-Trihydroxychalcone (isoliquiritigenin), a chalcone found in licorice root and shallots, exhibits antioxidant, estrogenic, and antitumor activities. To complement our previous studies concerning the phase 1 metabolism of isoliquiritigenin, the phase 2 transformation of isoliquiritigenin by human hepatocytes and pooled human liver microsomes (HLMs) was investigated using liquid chromatography/tandem mass spectrometry and UV absorbance. Five glucuronides were detected corresponding to monoglucuronides of isoliquiritigenin and liquiritigenin, but no sulfate conjugates were observed. The UDP-glucuronosyltransferases (UGTs) involved in the formation of the major glucuronide conjugates were identified using recombinant human UGTs in combination with liquid chromatography/mass spectrometry. UGT1A1 and UGT1A9 were the major enzymes responsible for the formation of the most abundant conjugate, isoliquiritigenin 4'-O-glucuronide (MG5), with Km values of 4.30 ± 0.47 and 3.15 ± 0.24 µM, respectively. UGT1A1 and UGT1A10 converted isoliquiritigenin to the next most abundant phase 2 metabolite, isoliquiritigenin 2'-O-glucuronide (MG4), with Km values of 2.98 ± 0.8 and 25.8 ± 1.3 µM, respectively. In addition, isoliquiritigenin glucuronides MG4 and MG5 were formed by pooled human intestine and kidney microsomes, respectively. Based on the in vitro determination of a 25.3-min half-life for isoliquiritigenin when incubated with HLMs, the intrinsic clearance of isoliquiritigenin was estimated to be 36.4 ml/min/kg. These studies indicate that isoliquiritigenin will be conjugated rapidly in the liver to form up to five monoglucuronides.

Address correspondence to: Richard B. van Breemen, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, 833 S. Wood St., Chicago, IL 60612-7231. E-mail: breemen{at}uic.edu






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